60 YEARS OF NEUROENDOCRINOLOGY Acromegaly · 60 YEARS OF NEUROENDOCRINOLOGY Acromegaly Cristina Capatina1,2 and John A H Wass3 1Department of Endocrinology, Carol Davila University

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Thematic ReviewC CAPATINA and J A H WASS Acromegaly 226 :2 T141–T160

60 YEARS OF NEUROENDOCRINOLOGY

Acromegaly

Cristina Capatina1,2 and John A H Wass3

1Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania2CI Parhon National Institute of Endocrinology, Bucharest, Romania3Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital,

Old Road, Headington, Oxford OX3 7LE, UK

http://joe.endocrinology-journals.orgDOI: 10.1530/JOE-15-0109

� 2015 Society for EndocrinologyPrinted in Great Britain

Published by Bioscientifica Ltd.

This paper is part of a thematic review sectiThe Guest Editors for this section were Ashl

Downloa

Correspondence

should be addressed

to J A H Wass

Email

[email protected]

Abstract

Acromegaly (ACM) is a chronic, progressive disorder caused by the persistent hypersecretion

of GH, in the vast majority of cases secreted by a pituitary adenoma. The consequent increase

in IGF1 (a GH-induced liver protein) is responsible for most clinical features and for the

systemic complications associated with increased mortality. The clinical diagnosis, based on

symptoms related to GH excess or the presence of a pituitary mass, is often delayed many

years because of the slow progression of the disease. Initial testing relies on measuring the

serum IGF1 concentration. The oral glucose tolerance test with concomitant GH

measurement is the gold-standard diagnostic test. The therapeutic options for ACM are

surgery, medical treatment, and radiotherapy (RT). The outcome of surgery is very good for

microadenomas (80–90% cure rate), but at least half of the macroadenomas (most

frequently encountered in ACM patients) are not cured surgically. Somatostatin analogs are

mainly indicated after surgical failure. Currently their routine use as primary therapy is not

recommended. Dopamine agonists are useful in a minority of cases. Pegvisomant is indicated

for patients refractory to surgery and other medical treatments. RT is employed sparingly, in

cases of persistent disease activity despite other treatments, due to its long-term side effects.

With complex, combined treatment, at least three-quarters of the cases are controlled

according to current criteria. With proper control of the disease, the specific complications

are partially improved and the mortality rate is close to that of the background population.

Key Words

" acromegaly

" diagnosis

" cure

" somatostatin analogs

" pegvisomant

" surgery

" radiotherapy

oney

ded

Journal of Endocrinology

(2015) 226, T141–T160

Introduction

Acromegaly (ACM) is a rare, slowly progressive disease

caused by a chronic excess of growth hormone (GH), and

associated with significant morbidity (Colao et al. 2004)

and increased mortality (Dekkers et al. 2008). Gigantism

occurs when the excess of GH becomes manifest in the

young, before the epiphyseal fusion.

Epidemiology

The estimated prevalence of the disease is 36–60

cases/1 000 000 population with three to four new cases

per 1 000 000 population per year (Alexander et al. 1980,

Bengtsson et al. 1988, Holdaway & Rajasoorya 1999,

Mestron et al. 2004). However, higher prevalence

(86/1 000 000) has been reported in a study involving an

active surveillance for pituitary adenomas (PAs; Fernandez

et al. 2010).

The sex ratio is close to 1 and ACM is typically

diagnosed in the fourth to fifth decade (Ezzat et al. 1994).

In virtually all cases ACM is caused by a GH-secreting PA.

PA are almost never malignant (Kaltsas et al. 2005) but

are associated with significant morbidity. ACM is also

on 60 years of neuroendocrinology.Grossman and Clive Coen.

from Bioscientifica.com at 08/31/2021 12:37:16PMvia free access

http://joe.endocrinology-journals.org

http://dx.doi.org/10.1530/JOE-15-0109

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Thematic Review C CAPATINA and J A H WASS Acromegaly 226 :2 T142

associated with a higher all-cause mortality compared

to the general population (mean standardized mortality

ratio (SMR) 1.72 (Dekkers et al. 2008)), mainly caused by

cardiovascular complications (Swearingen et al. 1998,

Mestron et al. 2004). Mortality rates are greater in patients

treated with radiotherapy (RT; Ayuk et al. 2004, Mestron

et al. 2004) and lower in those offered surgery as primary

treatment (Dekkers et al. 2008). Reduction of GH and

insulin-like growth factor 1 (IGF1) following treatment is

associated with a decrease of the SMR, toward normal

levels (Holdaway et al. 2008).

Pathogenesis

Most cases of ACM occur as a result of a sporadic GH-

secreting PA. However, ACM can occur in a familial

setting, either associated with other endocrine abnormal-

ities (in multiple endocrine neoplasia syndrome type 1,

McCune–Albright syndrome (Weinstein et al. 2001), and

Carney complex (Stratakis & Horvath 1993)) or as an

isolated disorder. This last condition is called familial

isolated PA (FIPA); 15% of these cases harbor germline

mutations of the AIP gene (encoding the aryl-hydrocarbon

receptor interacting protein), but the responsible gene

mutation is unknown in the majority of cases (Daly et al.

2007). GH-producing PA are the most frequent tumor type

in both AIP mutation positive and negative FIPA cases

(Cain et al. 2010).

Patients with apparently sporadic ACM harboring AIP

gene mutations (3% in a cohort of 154 cases) are younger

Table 1 Genetic syndromes associated with acromegaly. Data fro

(2007), Georgitsi et al. (2007) and Agarwal et al. (2009)

Familial syndrome Responsible gene Clinical characterist

FIPA AIP in 20%Unknown in the

majority of cases

Young patients (!old at diagnosis)

Usually macroadenwith extrasellar e

Less frequently consurgery or SSA

MEN type 1 MEN1 (menin) 11q13in 75–80%

CDKN1B in a minorityMcCune–Albright

syndromeGNAS 20 q13

Carney complex PRKAR1A 17q22–24



(Cazabat et al. 2007) and have larger, more invasive tumors

than do patients without mutations (Cazabat et al. 2012).

Also, FIPA cases with confirmed AIP mutation are younger

at diagnosis than both AIP-negative FIPA and sporadic

cases (Daly et al. 2010, Igreja et al. 2010).

Genetic syndromes associated with ACM are sum-

marized in Table 1. Specific gene mutations have been

described in these cases; the prevalence of these mutations

in sporadic tumors (without family history, without

associated abnormalities) is much lower (1–5% harbor

menin mutations (Agarwal et al. 2009) and 4% AIP

mutations (Cazabat et al. 2012)).

The pathogenesis of sporadic cases is more elusive.

The tumorigenesis of PA is complex and implies various

abnormalities in growth factor expression and cell cycle

control regulation (Boikos & Stratakis 2007a). Various

mutations or alterations in the expression of cell-cycle

genes, oncogenes or suppressor factors have been

described. For instance, somatic activating mutations of

the G-protein subunit alpha (Gs) are found in up to 40%

of GH-secreting PA; these cases are more responsive to

medical treatment with somatostatin (SS) analogs (SSA)

(Barlier et al. 1998). Also, pituitary tumor-transforming

gene (PTTG) is overexpressed in PA, including GH-

secreting, and its expression may be associated with

tumor invasiveness (Li et al. 2014).

Ectopic GH production from either ectopic PA or

extrapituitary tumors (pancreas, lung, and ovary) is an

exceptional occurrence (Melmed 1991). Ectopic secretion

of GH-releasing hormone (GHRH) has been very rarely

m Pellegata et al. (2006), Boikos & Stratakis (2007b), Daly et al.

ics

Other endocrine

abnormalities

Non-endocrine

abnormalities

40 years

omas,xtensiontrolled by

None None

Pancreatic neuroendocrinetumors

Parathyroid adenomasPrecocious pubertyThyrotoxicosisCushing’s syndrome

Polyostotic fibrousbone dysplasia

Cafe-au-lait skinpigmentation

Primary pigmented nodu-lar adrenocorticaldisease (PPNAD)

Thyroid nodules (benign/malignant)

MyxomasSkin pigmentationGonadal tumors

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Table 2 Clinical manifestations of acromegaly. Data from

Jadresic et al. (1982), Molitch (1992), Ezzat et al. (1994), Mestron

et al. (2004) and Reid et al. (2010)

Clinical effects of hormone hypersecretion

Skin Thick, oily skin

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reported, mainly originating from pancreatic or pulmon-

ary neuroendocrine tumors, but also hypothalamic

tumors (gangliocytoma). In such cases the pituitary

gland can be enlarged and only the serum measurement

of the GHRH level can lead to the positive diagnosis

(Borson-Chazot et al. 2012).
Hyperhydrosis – 65%Skin tagsAcanthosis nigricans
Musculoskeletalsystem

Somatic changes (prognathism, frontalbossing, and acral enlargement) –96–98%

Arthralgias, osteoarthritis – 24%Chronic painHearing lossMyopathyDecreased bone quality, vertebral

fracturesCardiovascular Arterial hypertension – 40%

CardiomyopathyVentricular hypertrophyArrythmiasCongestive heart failure

Metabolic Diabetes mellitusGlucose intolerance

Gastrointestinal Colon polypsDental changes (separation;

jaw malocclusion)Respiratory system Sleep apnea

Upper airway obstructionMacroglossia

Visceromegaly GoiterMacroglossia

Pathology

GH-secreting PA can be classified into two histological

subtypes based on the distribution of cytoplasmic cytoker-

atin: densely granulated (DG) and sparsely granulated

(SG). SG subtypes occur in younger patients, are larger,

more invasive, and less responsive to SSA (Larkin et al.

2013). Various other invasiveness and/or tumor aggres-

siveness markers have been proposed. The MAB MIB1

labelling index and the Ki-67 nuclear antigen expression

are used routinely (Jaffrain-Rea et al. 2002); both are higher

in SG than in DG tumors and inversely correlated with the

response to SSA (Kasuki et al. 2013, Sarkar et al. 2014).

Other markers (e.g., vascular endothelial growth factor

(Yarman et al. 2010) or PTTG expression (Zhang et al.

1999)) are mainly used in research protocols.

One-third of patients with pituitary tumors may have

mixed GH and prolactin (PRL) secreting adenomas (Reddy

et al. 2010).

CardiomegalyHepatomegalySplenomegaly

Neurological Carpal tunnel syndromeCerebral aneurysmsHeadache – 55%

General Decreased QoLLocal tumor effects Visual (visual field defects,

cranial nerves palsy)Headache – 55%Hypopituitarism

Clinical features and complications

The clinical presentation of ACM patients includes

symptoms and signs attributable to the hormonal

hypersecretion or the pituitary mass. The typical symp-

toms and signs are listed in Table 2 and they lead to the

positive diagnosis in 35% of cases. A similar percentage is

diagnosed incidentally while examining the patient for an

unrelated complaint (Alexander et al. 1980). Because the

average time from symptoms onset to diagnosis is usually

about 7–10 years (Rajasoorya et al. 1994), at the time of

diagnosis many patients present with specific compli-

cations of the disease. The most prevalent comorbidities

are arterial hypertension, sleep apnea, impaired glucose

tolerance (IGT), and diabetes mellitus (DM) (Mestron

et al. 2004).

Complications

Cardiovascular Arterial hypertension is among the most

frequent complications in ACM cases, present in 36–40%

of patients (Mestron et al. 2004, Reid et al. 2010).

Valvulopathies and arrhythmias are also more prevalent



in ACM populations (Colao et al. 2004, Pereira et al. 2004).

Almost a half of a small cohort of ACM patients presented

complex ventricular arrhythmias (Lown III–IV) in one

study, especially those with a long disease duration

(Kahaly et al. 1992). A multicentric study performed in

Italy using 24-h ECG-Holter monitoring reported a lower

but still very significant rate of ventricular extrasistoles

(in 33% of the ACM cases evaluated; Lombardi et al. 2002).

Twenty-four-hour ECG-Holter monitoring might be useful

in the preoperative evaluation of the patients (Fedrizzi &

Czepielewski 2008), especially those with clinically

detected abnormalities.

If untreated, the presence of these significant morpho-

logical and functional changes leads to a complex





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cardiomyopathy characterized by concentric hypertrophy

(predominantly affecting the left ventricle, found hyper-

trophic in 60% of cases (Colao et al. 2004)), diastolic

dysfunction and progressive systolic impairment even-

tually leading to heart failure (Mosca et al. 2013).

Other cardiovascular risk factors are also present in

ACM (elevated triglycerides, lipoprotein-a, fibrinogen,

plasminogen activator inhibitor, and small dense LDL

particles; Tan et al. 1997, Colao et al. 2004). Although the

prevalence of coronary artery disease is not clearly

increased in ACM patients and most patients belong to

the low-risk category if assessed with the Framingham

score (Bogazzi et al. 2007), aggressive management of all

cardiovascular risk factors is indicated, aiming at reducing

the cardiovascular morbidity and mortality (Katznelson

et al. 2014).

Metabolic ACM is frequently associated with IGT and

DM because the GH excess is associated with insulin

resistance (in the liver and in periphery), hyperinsuline-

mia, increased gluconeogenesis, and decreased peripheral

glucose uptake (Møller et al. 1991). DM prevalence has

been variably reported (reflecting the series heterogeneity

with respect to ethnicity, disease status, age, etc.), but the

highest prevalence rates were 40–52% (Biering et al. 2000,

Dreval et al. 2014); similarly, IGT can be found in up to

28–46% of cases (Biering et al. 2000, Kasayama et al. 2000).

The GH-lowering effect of some of the treatment

methods used in ACM (surgery, pegvisomant (PEG))

improves the glucose tolerance (van der Lely et al. 2001,

Mori et al. 2013), while others (SSA) have a modest

deleterious effect (Mazziotti et al. 2009).

Respiratory Sleep apnea (manifested as snoring, dis-

turbed night sleep with somnolence during the day) has

been variably reported in from 13% (Mestron et al. 2004)

to over 50% of cases (van Haute et al. 2008), more

frequently in diabetic or hypertensive cases (van Haute

et al. 2008). Most cases have obstructive sleep apnea

(mediated by the GH-related soft tissue growth around the

upper airways), and a minority of cases have either pure

central apnea or mixed apnea (Roemmler et al. 2012).

Some patients have respiratory dysfunction despite

elevated vital capacity (Trotman-Dickenson et al. 1991).

Upper airway obstruction is common (due to soft tissue

swelling, macroglossia) and can lead to difficult intubation

at the time of surgery.

Skeletal Acromegalic arthropathy can affect up to

84% of the cases (depending on the affected joint; Miller



et al. 2008), especially older patients or females (Kropf et al.

2013). Carpal tunnel syndrome occurs in 20–40% of cases.

Musculoskeletal pain is extremely prevalent and adversely

impacts the quality of life (QoL; Miller et al. 2008).

GH has anabolic bone effects so bone mass is usually

increased compared to normal subjects (Kaji et al. 2001),

unless untreated hypogonadism is also present. However,

a recent meta-analysis of the literature revealed a high risk

of vertebral fractures in active ACM suggesting a possible

low quality of the bone despite a high bone mass

(Mazziotti et al. 2015).

Neoplastic ACM has been associated with an increased

risk of certain tumors, presumably due to the stimulatory

effect of the IGF1 on tumorigenesis. The best-documented

data are those regarding colorectal neoplasia. The pooled

odds ratio (OR) are increased for both benign tumors (2.48

for adenomas and 3.557 for hyperplastic polyps) and

colon cancer (2.04–4.351) (Renehan et al. 2003, Rokkas

et al. 2008). The SMR for colon cancer is also higher in

active ACM (2.47) compared to the general population

(Orme et al. 1998).

The precise mechanism for the increased risk of colon

tumors is not known. Potential mechanisms include

direct GH or IGF1 actions on the colonic epithelial cells,

altered bile acids secretion pattern, impaired immune

response mechanisms in the colon mucosa, and increased

colonic length – reviewed extensively elsewhere (Renehan

et al. 2003).

The timing of the baseline colonoscopy is still

debated. Some only consider it at 50–55 years (Renehan

et al. 2001), but even younger patients harbor colonic

tumors, so initial colonoscopy at ACM diagnosis has been

suggested (Terzolo et al. 2005). Repeated colonoscopy

every 10 years in controlled ACM with a normal initial

result and every 5 years in those with benign tumors or

uncontrolled disease appears reasonable (Dworakowska

et al. 2010).

The risk of thyroid nodular disease and thyroid cancer

is also increased, with an OR of 6.9 and 7.5, respectively,

and a prevalence of 59 and 4.3% respectively (Wolinski

et al. 2014). Whether this reflects a specific effect of the

GH/IGF1 excess or the increased worldwide availability

and use of precise diagnostic techniques is controversial.

Only a circumstantial relationship between ACM and

prostate or breast cancer has been described to date. Until

large epidemiological studies to clarify this relationship

become available, it seems prudent to offer prostate

cancer surveillance to older uncontrolled male patients





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and routine breast cancer prevention in females (Webb

et al. 2002).

Other Some degree of hypopituitarism is present in up

to three-quarters of the patients at diagnosis (as most

GH-producing adenomas are macroadenomas; Nomikos

et al. 2005).

As a consequence of the multiple comorbidities and

the somatic changes, ACM patients have severely impaired

QoL (Webb 2006), psychological impairment, increased

anxiety and decreased self-esteem (Pantanetti et al. 2002).

Diagnosis

The biochemical diagnosis of ACM requires the confir-

mation of persistently elevated serum levels of GH and

IGF1 (a GH-regulated protein synthesized mainly in the

liver; Le Roith et al. 2001). In many cases the biochemical

diagnosis is straightforward because the serum levels of

both GH and IGF1 are markedly elevated. However, in a

minority of cases, mostly with mildly active disease, the

assessment can be challenging.

The random assessment of serum GH is rarely useful

due to the pulsatility of normal GH secretion; however,

Table 3 Tests used for the biochemical diagnosis of acromegaly. D

Duncan & Wass (1999), Hall et al. (1999), Freda et al. (2003), Arafat et

et al. (2012) and Katznelson et al. (2014)

Test Normal values

OGTTGive 75 g glucose orally to a fastingpatient

Measure serum GH at baseline, 30,60, 90, and 120 min

Suppressed GH levels: n!0.3 mg/l when usingsensitive GH assay

Nadir GH !1 mg/l accepassays

Mean GH day curveFive-point curve of serum GH duringthe day

!1 and 2.5 mg/l for minGH values

IGFINo test preparation needed Age- and sex-matched

are neededSample can be taken at any time Preferably use the sam

evaluation of the sam

TRH test200 mg of TRH intravenously

Serum GH measurement at 0, 20,and 60 min

Suppressed GH levels

Y, Decrease; [, increase.



a random serum GH level !0.4 mg/l together with a

normal IGF1 excludes the diagnosis (Giustina et al. 2000).

In contrast, IGF1 serum levels are stable during the

day and they have a good correlation with the GH levels

(Barkan et al. 1988). Measuring the IGF1 in serum is the

initial test indicated in all patients suspected of ACM on

clinical grounds or in cases with pituitary masses; selected

patients with several comorbidities commonly present in

ACM can also be tested (Katznelson et al. 2014). Active

ACM is associated with elevated IGF1 levels compared to

normal subjects (Ho & Weissberger 1994), so a normal

IGF1 (using age- and sex-matched reference ranges)

excludes the diagnosis in most patients (Katznelson et al.

2014). However, certain pathological conditions (see

Table 3), assay variability or inaccurate reference ranges

(Pokrajac et al. 2007) can lead to false negative results,

especially in mild cases.

The serum GH concentration measured during an oral

glucose tolerance test (OGTT) is the gold-standard

diagnostic test (showing the lack of normal suppression

of serum GH concentration during hyperglycemia) and

should be used to confirm the diagnosis in all cases with

high or equivocal IGF1 or in situations possibly interfering

with IGF1 measurement. The cutoff for nadir GH during

OGTT is highly dependent on the assay used. With the use

ata from Irie & Tsushima (1972), Clemmons & Van Wyk (1984),

al. (2008), Cordero & Barkan (2008), Frystyk et al. (2010), Minuto

Comments

adir belowa highly

table with most

Possible abnormal results in females,obese patients catabolic states

imum and mean Difficult, time-consumingRarely used

reference ranges Inter-assay variabilityInfluenced by age (Y with age), sex

(Y in women), pregnancy ([), nutritionalstatus (Y in malnutrition), liver and renalfailure (Y), and glucose metabolism(Y in DM)

e kit/lab for thee patient

Paradoxical rise (50% or more of the basalGH levels) in ACM

Rarely, if ever, used today





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of ultrasensitive GH immunoassays, in healthy individuals

the GH suppresses to very low levels after a 75 g glucose

load (as low as 0.14 mg/l; Freda et al. 1998a). However,

using such a low cut-off would only be applicable to

ultrasensitive GH assays. Therefore, the current guidelines

suggest that, because many GH assays currently used

worldwide do not have adequate accuracy at low GH

levels, a cutoff for nadir GH during OGTT below 1 mg/l is

acceptable for excluding the diagnosis (Katznelson et al.

2014). However, it should be borne in mind that using this

cutoff could lead to the inaccurate exclusion of the

diagnosis in a significant percentage of cases with mild

active disease (Dimaraki et al. 2002, Freda et al. 2003).

Indeed, many cases of active mild ACM exhibit significant

GH suppression during OGTT, as low as 0.33 mg/l (Freda

et al. 1998b).

The mean value of several samples taken a few hours

apart throughout the day can also be used (GH day curve

(GHDC)) as it is significantly correlated with the GH nadir

during OGTT (Dobrashian et al. 1993) and with the IGF1

level (Minuto et al. 2012). In normal subjects GH levels are

usually undetectable, except for several pulses of secretion

(mostly during the night; Duncan & Wass 1999, Peacey

et al. 2001). In ACM, nadir GH levels during a day-curve do

not suppress below 1 mg/l (as in normal subjects) and mean

integrated 24-h levels are significantly elevated (Ho &

Weissberger 1994), but the procedure is cumbersome and

rarely used.

Further complicating the diagnosis in cases with

mildly active disease (who could derive a great benefit

from an early diagnosis and treatment) are the frequent

(around 30% of cases) discrepancies between the GH and

IGF1 hypersecretion. Elevated IGF1 with normal GH status

may reflect earlier disease (Dimaraki et al. 2002) and

should prompt a thorough investigation (including

imaging) to clarify the diagnosis.

The major binding protein of IGFI, IGFBP3 is not

useful for diagnosis or treatment follow-up as significant

overlap occurs between normal controls and patients

(Wass 1997).

In the rare situation where a non-pituitary aetiology

is suspected, the serum GHRH level should be measured;

GHRH secretion is responsible for 0.5% of all cases (Losa &

Von Werder 1997).

PRL serum level should also be measured, as PRL may

be co-secreted with GH in up to a third of patients (Reddy

et al. 2010). Also, once the diagnosis is secured, a thorough

investigation of the pituitary function should be

performed.



Imaging

Once the biochemical diagnosis of ACM is made, the

documentation of the responsible PA (the most common

cause of ACM), its appearance and involvement of the

parasellar structures by contrast-enhanced magnetic reso-

nance imaging (MRI) or, when contraindicated or not

available, computed tomography (CT)-scan is required

(Katznelson et al. 2014). At diagnosis, most ACM patients

have a macroadenoma (73% in a national registry study

(Mestron et al. 2004)), sometimes with extrasellar extension.

The tumor usually appears hypointense on T1-weighted

MRI and has decreased contrast-enhancement compared to

the surrounding normal tissue. The hyperintense appear-

ance on T2-weighted MRI frequently corresponds to more

aggressive SG tumors (Hagiwara et al. 2003). In contrast, the

hypointense T2-weighted signal on MRI is indicative of

increased SSA responsiveness (Puig-Domingo et al. 2010).

Additional testing

Visual field assessment should be done in all cases of

macroadenoma close to the optic chiasm (Katznelson et al.

2014). Also, assessment of the pituitary function and

proper replacement of any deficient axes are mandatory.

Evaluating for most frequent comorbidities is rec-

ommended at diagnosis. Once the diagnosis of ACM is

confirmed, a baseline colonoscopy and thyroid ultrasound

are recommended; cardiological assessment including

echocardiography or Holter EKG exploration are indicated

if clinical findings are suggestive of cardiovascular

complications (Katznelson et al. 2014).

Treatment

Overview

Treatment of ACM is complex and aims to control

symptomatology, normalize the hormonal excess and

decrease the risk of complications, shrink or completely

remove the pituitary mass with minimal impairment of

the normal pituitary function. Treatment methods

include surgery, medical treatment, and adjuvant RT.

IGF1 levels are promptly normalized after successful

surgery or medical treatment (either with SSA (Lamberts

et al. 1988) or PEG (Trainer et al. 2000)) and this is

correlated with improvement of the signs and symptoms

of the disease (Clemmons et al. 1979).

Selective transsphenoidal adenomectomy is usually

the first-line treatment, especially in those with fully





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resectable tumors or with visual impairment (Giustina

et al. 2000). Medical treatment with SSA is usually initiated

in persistent disease after surgery; it can also be used in

selected cases as first-line treatment. With the progressive

development of efficacious, better-tolerated drugs, RT is

falling out of favor, being reserved to cases resistant to

other therapies.

Surgery

The surgical intervention aims to completely remove the

PA while preserving or restoring the pituitary function.

Transsphenoidal surgery using either the endoscopic or

microsurgical approach is the gold standard. Some studies

report substantially better outcomes for the endoscopic

approach (Dorward 2010), while others find no significant

difference in remission rates (Starke et al. 2013), so the

choice between them currently depends on the preference

and expertise of the surgical team. Craniotomy is very

rarely used.

Although the surgical results have overall improved in

the last decades (Bates et al. 2008), the experience of the

surgeon is still essential for surgical cure (Bates et al. 2008,

Schofl et al. 2013). In older series, disease remission using

milder criteria (defined as normal IGF1 and/or nadir GH

below 2 mg/l) was achieved in 61% of cases overall (88% for

microadenomas) (Freda et al. 1998b). When using current

biochemical remission criteria (see below), the best

reported rates for micro- and macroadenomas were 81–

100% and 45–68% respectively (Ludecke & Abe 2006, Jane

et al. 2011, Sun et al. 2014). In a large study based on the

German ACM Registry, reflecting the integrated results

obtained by different centers, the overall rate of IGF1

normalization by surgery alone was only 38.8% (Schofl

et al. 2013).

The chance of remission is inversely correlated with

tumor dimension, preoperative GH/IGF1 level, number of

operations (Sun et al. 2014), age (Abosch et al. 1998), and

invasion of adjacent structures – cavernous sinus invasion

indicates a tumor not fully resectable (Nomikos et al. 2005)

– and early postoperative GH level (Freda et al. 1998b). In

one study, male sex and parasellar extension (especially

cavernous sinus invasion) were the most powerful

predictors for persistent disease (van Bunderen et al. 2013).

Presurgical SSA administration has been reported to

improve surgical outcome and reduce complications

(Annamalai et al. 2013), but these findings were not

confirmed by other authors (Losa et al. 2006). Randomised

controlled studies exploring the potential benefits are

scarce (Carlsen et al. 2008, Mao et al. 2010, Shen et al. 2010,



Fougner et al. 2014). All involve small series treated for a

few months before surgery. Immediate results of surgery

are significantly better in pretreated cases (Carlsen et al.

2008, Mao et al. 2010, Shen et al. 2010), but the long-term

results are conflicting: some authors report no difference

(Shen et al. 2010) while others report a slightly higher cure

rate in the pretreated group at 5 years follow-up (41% vs

27%) (Fougner et al. 2014). In a recent meta-analysis,

the chance of surgical remission (GH nadir after OGTT

!1 mg/l and normal age-matched IGF1) was overall higher

in pretreated patients (Nunes et al. 2015). However, the

extent and quality of the currently available evidence

supporting the routine use of presurgical SSA are low, so it

is not recommended as a routine approach (Katznelson

et al. 2014). It can be used for specific patients (invasive

macroadenomas with low probability of surgical cure,

severe complications) for a few months (Melmed et al.

2009, Jacob & Bevan 2014, Katznelson et al. 2014).

SSA pretreatment can also be useful in individual patients

with severe soft tissue overgrowth (associated with

intubation difficulties and complications) as it reduces

the anesthetic complications and facilitates intubation

(Friedel et al. 2013).

Surgical debulking also improves later control by SSA

(Wass 2005, Karavitaki et al. 2008; not unexpected, as

responsiveness to SSA is inversely correlated with pretreat-

ment disease burden; Bhayana et al. 2005). Therefore,

surgery is indicated also in cases deemed surgically

incurable at diagnosis, in order to improve the response

to medical treatment (Katznelson 2010).

In addition to the increased chance of cure in

experienced surgical centers, surgery also provides a

tumor sample for pathological and immunohistochemical

examination. Complications of surgery are usually minor

(nasal congestion, sinusitis, epistaxis, and taste or smell

abnormalities). Cerebrospinal fluid leak can occur in 2–5%

of the cases (Nomikos et al. 2005, Tabaee et al. 2009). Major

complications (meningitis, visual impairment, and carotid

artery injury) occur in !1% of the cases in experienced

pituitary centers. Mortality is reported in about 0.1% of

the cases operated in dedicated centers (Nomikos et al.

2005). The pituitary function is improved in almost half of

the operated cases. Worsening of the pituitary function is

reported in a minority of cases operated transsphenoidally

but occurs in a quarter of those rare cases approached

transcranially (Nomikos et al. 2005). Diabetes insipidus

(DI) can occur in a minority of patients, mostly transient,

with !2% chance of permanent DI (Abbassioun et al.

2006, Tabaee et al. 2009).





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The long-term recurrence rate following apparent

successful initial surgery is generally low (0.4–1.1%;

Kreutzer et al. 2001, Nomikos et al. 2005), but in some

series recurrence rates of 10% at 15 years have been

reported (Swearingen et al. 1998), probably reflecting the

inherent low growth rate of small unresected remnants.

Recurrences peaked between 1 and 5 years after surgery.

A low postoperative hormone concentration is correlated

with a decreased recurrence risk (Roelfsema et al. 2012).

Patients with remission should be reevaluated yearly, and

those with persistent disease should receive medical

treatment (Katznelson et al. 2014).

In view of its lower comparative costs, low compli-

cations rates and reasonable efficacy, surgery remains

the recommended primary treatment method in most

patients (Katznelson et al. 2014).

Medical treatment

Medical treatment is currently a mainstay of the complex

treatment of ACM. A large body of evidence proves its

efficacy, with various response rates depending on the

preparation, regimen used, patients characteristics and

so on.

SS analogs SSA are analogs with longer half-life of the

endogenous SS, acting on the SS receptors (SSR) in the

pituitary. The SSR belong to a family of G-protein-coupled

receptors with five members described (SSR1–5). GH-

secreting PAs frequently express SSR (mostly type 2;

Hofland & Lamberts 2001). Through their specific

interaction with these receptors, SSA exert antisecretory

and antiproliferative effects.

The SSA in use are octreotide (OCT) and lanreotide

(LAN). Initial OCT formulations (administered as three

daily s.c. injections) proved useful, resulting in significant

symptoms improvement and hormonal response in most

cases (Newman et al. 1995). Currently long-acting SSA

formulations are available (OCT long-acting release (OCT-

LAR), LAN sustained release (LAN-SR), and LAN autogel

(LAN-ATG)), and they represent the first-choice medical

treatment. The reported efficacy differs among various

studies, but there is also marked heterogeneity related to

treatment algorithm, case selection and definition of

remission; also, most studies lack a control arm.

As the surgical cure rates are still low in many GH-

secreting macroadenomas, postsurgical SSA are mainly

indicated in cases with persistent disease after surgery

(Katznelson et al. 2014). Overall, OCT-LAR reduced GH to

below 2.5 mg/l and normalized the IGF1 levels in 66 and



63% of cases, respectively, in a critical analysis of the

largest studies (Murray & Melmed 2008). The same targets

were achieved with LAN-SR in 52 and 47% of cases

respectively (Murray & Melmed 2008). In an earlier

meta-analysis, the overall chance of IGF1 normalization

was 67% with OCT and 47% with LAN-SR (Freda et al.

2005). Although LAN-SR appears slightly less efficacious,

there are several important caveats to be accounted for

(inclusion of both primary and secondary treated cases,

unclear dose optimization protocols, small number of

cases in the studies included). Also, some of the cases

included had been preselected for SSA responsiveness.

Preselection of responsive cases is usually based on prior

use, but the OCT suppression test (hourly GH measure-

ments for 6 h following 100 mg s.c. OCT) has also been

suggested. The overall predictive power of the test is,

however, suboptimal. The nadir GH during OGTT is

correlated with safe GH and IGF1 during OCT-LAR but

less so for LAN (Karavitaki et al. 2005). Also, the tumoral

response under SSA is only modestly correlated with the

OCT test (Annamalai et al. 2013).

As expected, the preselection is associated with higher

IGF1 normalization and tumor shrinkage rates (Freda et al.

2005). Consequently, in unselected cohorts the rate of

biochemical control was lower: 44% of cases treated with

OCT-LAR reach GH !2.5 mg/l and 34% a normal IGF1

after 48 weeks (Mercado et al. 2007).

With long-term SSA administration, a gradual further

improvement can be expected, with maximal benefit

achieved after more than 10 years of treatment (Maiza

et al. 2007). In a large national-registry-based analysis,

‘safe’ (!2 mg/l) GH levels were achieved with long-term

SSA treatment in 75%, normal IGF1 in 69% and both in

55% of cases. Adenomas with a DG cytokeratin pattern

(Larkin et al. 2013), high SSR2 and SSR5 expression

(Espinosa de los Monteros et al. 2014), low Ki-67 index

(Kasuki et al. 2012), as well as those previously subjected

to surgery and/or RT (Howlett et al. 2013) respond better

to SSA treatment.

Biochemical remission is the most important effect,

but tumor shrinkage also occurs. Published meta-analyses

revealed that OCT-LAR (Giustina et al. 2012) and LAN

formulations (Mazziotti & Giustina 2010) induce some

degree of tumor shrinkage in 66.0 and 32.8% of cases

respectively. Fifty-seven percent of patients treated with

OCT exhibit tumor shrinkage of at least 20%; the

mean computed degree of change induced by OCT-LAR

was around 50% (Giustina et al. 2012). In isolated

cases the shrinkage effect can be spectacular (Espinosa

de los Monteros et al. 2014). Tumor decrease is more





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frequent and significant in primary-treated patients and

in large macroadenomas (Mazziotti & Giustina 2010,

Colao et al. 2011).

The use of SSA as primary treatment was also

advocated as it proved to be efficacious in uncontrolled

studies (Cozzi et al. 2006). As primary treatment, SSA

induce a clinically significant degree of tumor shrinkage

in 36% of cases; the mean calculated percentage of tumor

reduction was about 50% in these responsive cases. If all

cases are taken into account, the overall tumor reduction

is 19% (Melmed et al. 2005). Primary SSA treatment is

associated with a lower remission rate compared to initial

surgery (45% vs 67% for surgery; Abu Dabrh et al. 2014).

To date, there are no robust data to support the routine

recommendation of primary SSA treatment. It can be

offered before surgery in patients with contraindications

or who refuse surgery (Melmed et al. 2005), in cases with

unresectable tumor (e.g., cavernous sinus invasion) or

with severe complications (Katznelson et al. 2014).

The preference for one SSA over another is not

currently substantiated. Biochemical control (Murray &

Melmed 2008) and tumor shrinkage (Freda et al. 2005)

appear slightly more frequently with OCT-LAR compared

to LAN-SR. However, this evidence does not come from

randomized head-to-head comparisons and is subject to

a number of biases and limitations, as discussed above.

Also, the two available LAN preparations (LAR and ATG)

induce similar results (Murray & Melmed 2008). Recently

the results of a phase III multicenter trial on the efficacy

of an oral OCT formulation showed that switching

from injectable SSA to the oral formulation effectively

maintains disease control in the majority of cases (Melmed

et al. 2015).

Withdrawal of SSA is possible in a small but distinct

subset of patients, particularly in those who are very well

controlled on relatively low doses administered at long

intervals (Ramirez et al. 2012). At SSA discontinuation,

tumor regrowth is possible within months (Ezzat

et al. 1992).

In contrast, a significant minority of the patients do

not achieve biochemical remission, even with long-term

treatment. The variable SSR5 expression may explain the

partial responsiveness to SSA in patients with adequate

SSR2 density in the cell membrane (Cuevas-Ramos &

Fleseriu 2014). In these cases, initiation of PEG or

cabergoline treatment is recommended (Katznelson

et al. 2014).

During SSA treatment, improvement of joint and soft

tissue symptoms as well as headache and perspiration

frequently occurs (Caron et al. 2004, Mercado et al. 2007).



Side effects are frequent but mostly of little severity.

Abdominal discomfort is frequent, especially at the

initiation of the treatment. Gallbladder sludge or gall-

stones are also common. Pancreatitis is rare (Neggers et al.

2007). SSA suppress plasma insulin levels and were

initially thought to aggravate the glucose intolerance;

however, the overall effect on glucose metabolism is not

clinically significant (Breidert et al. 1995), probably

because the effect on GH and consequently insulin

resistance predominates. A meta-analysis published in

2009 confirmed that, despite the decrease of fasting

insulin and possible alteration of glucose levels during

OGTT, fasting plasma glucose and HbA1c do not change

significantly, arguing against a clinically significant effect

(Mazziotti et al. 2009).

Pasireotide In patients inadequately controlled by classic

SSA (OCT and LAN), a new multi-SSR-targeted compound

(pasireotide), with high affinity for all human SSR types

except type 4 (Bruns et al. 2002), was investigated in

clinical studies.

Both pasireotide (Petersenn et al. 2014a) and pasireo-

tide LAR (Petersenn et al. 2014b) appear promising as

medical agents with antisecretory and antitumoral effect.

A comparison between pasireotide LAR 40 mg/28 days and

OCT-LAR 20 mg/28 days revealed that biochemical con-

trol (GH !2.5 mg/l and normal IGF1) after 12 months was

achieved in significantly more cases treated with pasireo-

tide LAR than with OCT-LAR (31% vs 19%). However, this

study had no robust protocol for dose up-titration, and

many patients in both groups did not receive a dose

increase, altering the conclusion that can be drawn from

the study (Colao et al. 2014).

Similar rates of biochemical control (27%) were

reported with pasireotide after 3 months of treatment;

39% of the cases also had a significant (O20%) decrease in

pituitary tumor volume (Petersenn et al. 2010). In the

study of Colao et al. (2014), almost 80% of the cases treated

for 1 year with either pasireotide or OCT LAR achieved a

significant tumor decrease (mean reduction 40%), both

postsurgical and de novo treated cases.

Pasireotide proved beneficial in a significant minority

of patients uncontrolled by SSA: 15 and 20% of the cases

treated with pasireotide LAR 40 and 60 mg, respectively,

achieved biochemical control after 24 weeks in a large

multicentric study (PAOLA; Gadelha et al. 2014).

However, hyperglycemia was recorded in 31–57% of

the cases evaluated in these two studies (Colao et al. 2014,

Gadelha et al. 2014). Currently pasireotide has not entered

into clinical use.





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Pegvisomant PEG is a GH receptor antagonist which

blocks the peripheral synthesis of IGF1 (Muller et al. 2004).

Initial trials demonstrated normalization of serum IGF1

concentration in 97% of the cases treated for at least 12

months (van der Lely et al. 2001). In real-life conditions

the response rates are lower. In a worldwide surveillance

study (Acrostudy) of patients treated only with PEG in

daily s.c. injections, IGF1 was normalized in only 67.5%

of cases after 3.8 years follow-up (Freda et al. 2014). The

efficacy increases slightly with time (Schreiber et al. 2007),

reaching 70.9% after 6 years (Grottoli et al. 2015). The

response is dose-dependent: 89% of cases treated with

20 mg PEG daily reach a normal IGF1 in 12 weeks (Trainer

et al. 2000). In clinical practice upward dose titration is not

always offered to cases with partial response to lower doses

(Freda et al. 2014), and this might explain suboptimal

response rates. With a more stringent dose titration

protocol 95% of the cases treated for a median duration

of 18 months can achieve IGF1 normalization under

current clinical care (Higham et al. 2009).

IGF1 normalisation is the main endpoint of treat-

ment; GH levels increase during treatment and cannot be

used for monitoring (van der Lely et al. 2001). Also, PEG

does not have an anti-tumoral effect, and initially there

was concern about the risk of tumor growth during

treatment. However, tumor increase is a rare event,

occurring in only 2.2% of cases (Freda et al. 2014).

The biochemical response to PEG leads to a significant

decrease of symptomatology (especially at doses higher

than 15 mg daily; Trainer et al. 2000). In contrast to SSA,

PEG decreases fasting plasma glucose (Urbani et al. 2013)

and improves glucose tolerance (Colao et al. 2006) and

insulin sensitivity (Schreiber et al. 2007). Switching from

SSA to PEG significantly improves diabetes control in

diabetic ACM cases (Barkan et al. 2005). However, an

indirect effect of the removal of previous SSA treatment

in SSA-resistant cases can contribute to this result.

PEG is usually administered as daily s.c. injections;

weekly or twice-weekly dosing (median doses 60 mg

weekly) is another effective option though not currently

in use (Neggers et al. 2009). It is generally well tolerated,

with adverse reactions in !10% of cases (increases in liver

enzymes, injection site reactions, and headache; Schreiber

et al. 2007). With combined SSA–PEG treatment for

4.5 years, transaminase levels increased in 27% of cases

(Neggers et al. 2009). However, with careful, continuous

monitoring, the combined PEG–SSA treatment is widely

used and highly effective: PEG added to patients uncon-

trolled by maximal doses of SSA normalize IGF1 in 95% of

cases (Neggers et al. 2009).



PEG treatment is currently recommended in cases

resistant or intolerant to SSA treatment (Herman-Bonert

et al. 2000) or in combination with SSA in partially

resistant cases (Katznelson et al. 2014). PEG is not

currently used routinely as primary medical treatment

but can be considered for this use in selected cases. For

instance, in ACM patients with severe DM, its use could be

safer due to its favourable impact on glycemic control

(Barkan et al. 2005).

Dopamine agonists Dopamine agonists (DA) are effica-

cious in a subset of ACM patients, especially those with

only mild GH hypersecretion (Howlett et al. 2013). Their

use in the treatment of ACM has consistently declined

in the last two decades, in parallel with the more frequent

use of other medical options. Therefore, many patients

currently treated with DA are those with proven respon-

siveness to this class of drugs before the widespread use of

other drugs. This explains the higher rate of efficacy in

current analyses. The large heterogeneity of the regimens

used also adds to the difficulty in assessing the outcome.

With these biases in mind, long-term DA treatment

achieved ‘safe’ GH levels in 50%, normal IGF1 in 36%,

and both in 26% of the cases evaluated after 2000 (Howlett

et al. 2013), a roughly similar percentage of success to that

achieved by SSA. In a systematic review assessing the

efficacy of cabergoline in ACM, the overall rate of

normalization was 34%. When added to SSA (in patients

with suboptimal control), 52% of the cases achieved

normal IGF1 levels (Sandret et al. 2011). When added to

PEG, cabergoline normalize IGF1 in 28% of cases with

partial response (Bernabeu et al. 2013). Consequently, the

use of cabergoline is recommended in patients with

inadequate response to other medical forms of treatment,

and the highest benefit is expected in cases with modest

persistent hormonal elevations (Katznelson et al. 2014).

The commonly held view that DA are more effective in PA

with mixed GH–PRL secretion is not supported (Cozzi et al.

2004, Sherlock et al. 2009).

Cardiac valve impairment secondary to cabergoline

use was described in long-term use of high doses

(recommended for Parkinson’s disease) but not in cases

treated with routine endocrinological doses (Samson &

Ezzat 2014).

Other treatment options Estrogens The addition of

estrogens or selective estrogen receptor modulators

(SERM) to the treatment was reported to offer additional

benefit, with greater reduction in IGF1 for estrogens

compared to SERM (Stone et al. 2014). Concurrent use of





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estrogens in ACM is not recommended by the current

guidelines, therefore their use can only be considered by

individual medical judgement in selected female patients

(especially resistant to other available therapies) after

a thorough evaluation of all possible risks and

contraindications.

Other options Trials are under way to assess the efficacy and

safety of several other molecules or formulations: new SSA

(targeted at more receptors types), chimeric molecules,

with specificity for both SSR and dopamine receptors

(dopastatins), and oral delivery of currently used SSA

(Cuevas-Ramos & Fleseriu 2014). In the future these

alternative drugs could become clinically available,

expanding the therapeutic armamentarium.

Radiotherapy The benefits of RT (tumor shrinkage and

decreased hormonal secretion) must be weighed against

the long latency of the effect and the high risk of adverse

effects, especially pituitary dysfunction. As new, effective

medical options with less side effects appeared, RT has

fallen out of favor and is currently reserved for patients

with persistent disease despite surgery and/or medical

treatment or if medical treatment is not tolerated or

unavailable (Katznelson et al. 2014).

Conventional fractionated RT (mean doses of

45–50 Gy) is associated with a very slow onset of effects

(5–15 years until maximal benefit), but eventually the

tumor control is about 95% (Minniti et al. 2005a) and the

biochemical response reported in series with long-term

follow-up (up to 20 years) is very good: 60–77% (Biermasz

et al. 2000, Minniti et al. 2005a, Jenkins et al. 2006).

However, very high rates of new hypopituitarism (77%)

are reported (Minniti et al. 2005a). With long (more

than 10 years) follow-up, in some series almost all

patients developed hypopituitarism (Littley et al. 1989,

Langsenlehner et al. 2007). Newer stereotactic techniques

(single-dose stereotactic radiosurgery (SRS) fractionated

stereotactic RT) have improved efficacy and reduced the

frequency of side effects due to the more localized delivery

of radiation (Minniti et al. 2012). SRS can be given either

by linear accelerator or by cobalt unit (gamma-knife (GK)).

The rates of both biochemical and tumor response are very

variably reported in the literature: 17–82% and 37–100%,

respectively, as reported in a critical analysis of the

literature (Stapleton et al. 2010). This high variability can

be attributed to different treatment schedules, criteria of

cure or follow-up durations. GK treatment induces tumor

shrinkage in about 60–75% of cases (Jezkova et al. 2006,

Lee et al. 2014a) at 5–6 years and the percentage continues



to increase slowly up to 82% at 8 years (Lee et al. 2014a).

The biochemical control rate is more difficult to be

appreciated because various control criteria were used; a

crude estimate from the largest studies published suggest

biochemical control with GK in about 48% after a mean

follow-up of 4 years (Newell-Price 2009).

The use of SSA possibly decreases the success of SRS

(Pollock et al. 2002), so temporary interruption of the

medical treatment before RT is suggested. In contrast, in

the interval until RT becomes efficacious, the use of SSA

is recommended (Melmed et al. 2009).

The prevalence of hypopituitarism with stereotactic

techniques is considerably lower. Overall radiation-based

treatment in mixed series induces hypopituitarism in

almost half of the patients over a long follow-up (Jallad

et al. 2007). In cohorts treated solely with stereotactic

methods variable rates of hypopituitarism have been

reported from below 10% at 3.8 years (Attanasio et al.

2003) to 31% at 8 years (Lee et al. 2014a), 12–20% in most

series (Milker-Zabel et al. 2001, Pollock et al. 2002, Wilson

et al. 2013), especially in large tumor masses (Pollock et al.

2002, Beauregard et al. 2003). Owing to the possibility of

late hypopituitarism, long-term follow-up and periodic

testing are mandatory after RT.

Apart from hypopituitarism, other major compli-

cations are possible following RT. Second brain tumors

have been described long before exposure (2–30 years) in

2.4% of cases (Minniti et al. 2005b). The prevalence of

cerebrovascular accidents increases with time from

exposure: 4% at 5 years, 11% at 10 years, and 21% at 20

years (Brada et al. 1999). Rarer occurrences are optic

neuropathy (also occurring about 15 years after irradiation

in 1–2% of cases; Fernandez et al. 2009) and brain necrosis

– an exceptional side effect. As most of these compli-

cations become apparent many years after the irradiation,

more data are available about conventional RT. Prolonged

follow-up of patients who underwent stereotactic RT in

the last decades will clarify the risks following these

procedures. Rare complications of SRS are cranial nerves

deficits, headache, radiation necrosis, carotid artery

stenosis, and trigeminal neuralgia (Beauregard et al.

2003, Stapleton et al. 2010). The risk of visual compli-

cations limits the use of SRS to lesions more than 3 mm

away from the optic structures (Petrovich et al. 2003). To

date, if RT is indicated, stereotactic methods should be

applied, unless the tumor remnant is large or close to the

optic apparatus (Katznelson et al. 2014).

Favorable prognostic factors for remission included a

higher margin radiation dose, higher maximum dose and

lower initial IGF1 level (Lee et al. 2014a). The remission





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rates are similar in SG and DG tumors. For SG adenomas,

which respond less well to medical therapy, earlier SRS

may be reasonable for consideration (Lee et al. 2014b).

Follow-up under treatment

The real efficacy of the treatment in ACM is difficult to be

interpreted due to the variability in the assays used,

follow-up interval, definition of biochemical response

as well as the inclusion of both naıve and preselected prior

responders. Overall, in real-life conditions, the data from

the large UK register suggest that only 75% of the cases

receiving medical GH-lowering treatment (SSA and/or DA)

are adequately controlled (Howlett et al. 2013).

The best test used to assess the disease status also

depends on the treatment offered to the patient. In the

first 3 months after surgery GH suppression is more useful

than IGF1 in predicting remission (Feelders et al. 2005);

immediately after surgery OGTT or GHDC can be per-

formed, with OGTT being more cost-efficient (Karavitaki

et al. 2009). Also, a morning fasting GH sample has a very

good positive predictive value for disease cure or control

(Karavitaki et al. 2009). A fasting GH below 2 mg/l on the

first postoperative day is predictive for remission (Krieger

et al. 2003).

In patients receiving SSA, OGTT is not useful in

assessing biochemical control. In these patients, both

basal and post-glucose GH levels are highly discordant

with serum IGF1 concentrations (Carmichael et al. 2009).

A random GH or mean GHDC can be used (Giustina et al.

2010), and normalization of IGF1 is an essential marker

of biochemical control in SSA-treated cases (Katznelson

et al. 2014).

During treatment with PEG, no direct measure of GH

secretion is useful (due to possible increase of secretion as

a result of negative feedback, as well as cross-reactivity

between the drug and some diagnostic assays; Muller et al.

2004). Instead, IGF1 normalization is the only marker of

disease control (Giustina et al. 2010).

Defining cure/remission

The biochemical definition of disease remission or cure is

difficult: nadir GH during OGTT, mean GH during GHDC

and IGF1 have been widely used but with many problems

related to the assay, reference ranges or cutoffs used. As

the definitions are still controversial, it is essential to

maintain, whenever possible, the same biochemical assays

throughout the management of an individual patient

(Katznelson et al. 2014).



Optimal disease control is currently defined as normal

age-adjusted IGF1 level and a random GH !1 mg/l or nadir

GH in OGTT !0.4 mg/l (Giustina et al. 2010, Katznelson

et al. 2014). Active disease is biochemically characterized

by random GH O1 mg/l and nadir GH in OGTT R0.4 mg/l

with elevated IGF1 (Giustina et al. 2010).

The cutoff for the nadir GH is highly assay-dependent;

when highly sensitive assays (now more readily available

worldwide) are used, up to 50% of patients with active

ACM have nadir GH values below 1 mg/l (Freda et al.

1998a). Some authors proposed a 0.25 mg/l cutoff to

differentiate the persistent disease activity (Serri et al.

2004). An even lower cutoff was advocated by some

authors who reported that 25% of postsurgical cases with

normal IGF1 and nadir GH O0.14 mg/l experienced

recurrence (Freda et al. 2004). If such very low cutoffs for

nadir GH are used, only a minority of treated cases can be

declared cured (Freda et al. 1998a), and in this group

hypopituitarism is more likely (Costa et al. 2002). Less

stringent endpoints might be better related to normal age-

matched IGF1 concentrations (Costa et al. 2002) and also

have meaningful effects in terms of disease-related

morbidity and mortality. Mean basal GH levels below

2.5 mg/l and normal IGF1 levels restore the SMR to that of

healthy controls (Bates et al. 1993, Orme et al. 1998,

Holdaway et al. 2003). Therefore, in clinical practice,

aiming for ‘safe’ values, such as those recommended by

the current guidelines, is more realistic.

Further complicating the matter is the frequent

occurrence of discordant GH and IGF1 levels after or

during treatment (Wass 1997, Carmichael et al. 2009). The

significance and natural history of these cases is not fully

understood. In many (39%) cases with normal IGF1, the

GH suppression in OGTT is abnormal if assayed with a

highly sensitive assay (Freda et al. 1998a). Some of these

cases are the result of persistent dysregulation of GH

secretion (Ho & Weissberger 1994) leading to minor GH

elevations which do not uniformly increase the IGF1

concentration (Clemmons 2005). In others, persistent

elevations of GH despite normal IGF1 are associated

with a higher recurrence risk (Freda et al. 2004). Also,

very low GH but elevated IGF1 can be encountered in

persistent disease (Freda 2003). In cases with discrepant

results, GHDC could be useful (Melmed et al. 2009,

Giustina et al. 2010).

Disease control is not always associated with optimal

control of the complications, despite overall improvement

and decrease in mortality (Holdaway et al. 2003). For

instance, in the presence of discordant serum IGF1 and

nadir GH levels, IGF1 is more predictive than GH levels of





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insulin sensitivity and clinical symptom score (Puder et al.

2005). It is also not clearly established whether both GH

and IGF1 cutoffs are necessary to normalize mortality.

In one analysis both random serum GH !2.5 mg/l or a

normal adjusted IGF1 level following treatment were

associated with mortality close to expected levels (SMR

1.1; Holdaway et al. 2008). In contrast, the effect of IGF1

could not be demonstrated by other studies (Sherlock et al.

2010). It remains unclear whether the control of GH, but

not IGF1, observed in many patients, is sufficient to restore

long-term morbidity and mortality to normal.

Long-term results of the treatment

With complex, combined treatment (see Fig. 1), 75–94%

of the cases are controlled according to current criteria

(Biermasz et al. 2004, Abbassioun et al. 2006, Schofl et al.

Confirmed ACM diagno

Surgery

IGF1 at 12 weeks + random

Undetectable

Remission

Monitoring

Increased IGF1 and GH

OGTT

Discordant: nadir GH <1µg/lPers

Start SSA; as

Controlled

Continue treatment andmonitoring

Not co

• Add DA, especially if

• Add PEG

• Consider PEG alone

• Consider further surg

Figure 1

Algorithm of treatment in ACM.



2013). Disease control is associated with significant

improvement of the symptomatology (Swearingen et al.

1998, Beauregard et al. 2003) and QoL (Caron et al. 2014).

With IGF1 normalization, resolution of symptoms and

partial improvement of specific ACM complications also

occur (Clemmons et al. 1979, Holdaway et al. 2003).

Glucose metabolism abnormalities are potentially revers-

ible with successful surgery (Mori et al. 2013) or PEG

treatment (van der Lely et al. 2001). Biochemical control is

associated with a lower prevalence of DM (Reimondo et al.

2014), partial improvement of the cardiac dysfunction and

increase in the cardiac performance (Mosca et al. 2013).

Hypertension, valvulopathy (Colao et al. 2004), sleep

apnea (Roemmler et al. 2012), joint complaints and related

decrease in QoL (Biermasz et al. 2005) and overall affected

QoL (Webb 2006) persist in a high percentage of patients

with even controlled disease.

sis

Individual SSA presurgery (severecomplications, decreased likelihood

of cure) or as primary treatment(contraindications for surgery)

GH

istent disease

Discordant

Repeat IGF1 later;perform OGTT

sess IGF1 prior to next dose

ntrolled

mild disease

if severe DM

ical debulking if

Not tolerated

Start PEG

Controlled

Continue treatment andmonitoring

Not controlled

Consider radiotherapy (SRS if not close to opticsystem)

Continue medical treatment until radiotherapybecomes effective





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The increased mortality associated with active,

persistent disease returns to expected values in cured

patients, while persistent disease is still associated with a

SMR of 1.8 (Swearingen et al. 1998). High post-treatment

GH levels are associated not only with an increased overall

mortality rate but also increased mortality rates due to

colon cancer, cardiovascular disease and all malignant

disease (Orme et al. 1998).

Conclusions

Tight biochemical control of ACM is essential to reduce

morbidity and to decrease the mortality rates to the level

of the general population. Optimal implementation of

current protocols in routine clinical practice and maximal

use of the medical treatment options could improve the

long-term control of patients with significant benefits for

morbidity and mortality.

Declaration of interest

The authors declare that there is no conflict of interest that could be

perceived as prejudicing the impartiality of the review.

Funding

This review did not receive any specific grant from any funding agency in

the public, commercial or not-for-profit sector.

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Received in final form 10 June 2015Accepted 25 June 2015Accepted Preprint published online 1 July 2015



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60 YEARS OF NEUROENDOCRINOLOGY Acromegaly · 60 YEARS OF NEUROENDOCRINOLOGY Acromegaly Cristina Capatina1,2 and John A H Wass3 1Department of Endocrinology, Carol Davila University